Proteoglycans are macromolecules distributed in the body. Proteoglycans can be found intracellular, on the surface of the cells and in the extracellular matrix. Proteoglycans represent a special class of glycoproteins that are heavily glycosylated. They consist of a core protein with one or more covalently attached glycosaminoglycan chain(s). These glycosaminoglycan (GAG) chains are long, linear carbohydrate polymers that are negatively charged under physiological conditions, due to the occurrence of sulphate and uronic acid groups.
Heparan sulphate proteoglycans (HSPG) is one group of proteoglycans. These comprise repeating disaccharides (GAGs) of D-glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc) linked to a core protein. The size of an individual GAG can reach 100 kDa. The GAGs are highly negatively charged due to the presence of sulphate or carboxyl groups or both on many of the sugar residues, resulting in that the HSPGs are overall negatively charged.
Glycosaminoglycans (GAGs) or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. This unit consists of an N-acetyl-hexosamine and a hexose or hexuronic acid, either or both of which may be sulfated. Members of the glycosaminoglycan family vary in the type of hexosamine, hexose or hexuronic acid unit they contain (e.g. glucuronic acid, iduronic acid, galactose, galactosamine, glucosamine). They also vary in the geometry of the glycosidic linkage. This family of carbohydrates is essential or important for the life of vertebrates and of various lower animals.
GAGs form an important component of connective tissues.
An upregulation of proteoglycans is associated with various diseases and conditions such as Alzheimer's disease, aneurismal aortas, atherosclerosis, hepatic fibrosis, microvascular endothelia and cancers such as breast cancer, cervical cancer, colon carcinoma, colorectal cancer, pancreatic cancer, prostate cancer and Wilm's tumour.
A number of research groups have been active in finding product and procedures for the identification of proteoglycans in vivo as illustrated by the following publications:
WO 00/23109 (The Regents of the University of California) proposes diagnostic agents for human cancers comprising a binding molecule, in particular an antibody, which is attached to a reporting molecule, and that binds to one of glypican-1 and to syndecan-1.
US 2002/0122806 (Chinnaiyan et al.) proposes a chimeric molecule, e.g. a recombinant polypeptide and a pharmaceutical composition comprising a fluorescent or chemiluminescent polypeptide and a chondroitin sulphate proteoglycan binding polypeptide and its use in diagnostic imaging.
WO 88/03413 (New England Deaconess Hospital) reads on a target seeking, biologically active molecule associated with an abnormality in the vascular system labelled with a radionuclide or a magnetic resonance imaging entity. The biologically active antibody has affinity e.g. for chondroitin sulphate proteoglycan and the antibody is preferably a monoclonal antibody.
WO 91/13919 (New England Deaconess Hospital) relates to peptides derived from vascular-associated protein having affinity for a vascular wall component which can be a proteoglycan and which can be labelled with a detectable label.
U.S. Pat. No. 6,991,778 (Nitrosci) proposes a MR imaging method for enhancing the imaging of joints using a water-soluble positive charged nitroxyl-functionalized dendrimer for visualisation of proteoglycans of the cartilage present in the joints.
Proteoglycans, and particularly HSPGs are attractive markers for diagnosis of various diseases as noted above. The efficient targeting and imaging of HSPGs demands a vector with high affinity for the target structure that is chemically robust and stable. These conditions are met by the compounds of the invention.